tbuckley/cabot-search huggingface dataset:
Abstract B019: Inflammatory response to dietary carbohydrates contributes to the formation of hepatic metastatic niche
Authors: Aizhan Surumbayeva, Riley Williams, Michael Kotliar, Maryclare Taylor, Débora B. Vendramini Costa, Charline Ogier, Diana Restifo, Kathy Q. Cai, Xueyang He, Paul Boutz, Siddharth Balachandran, Igor Astsaturov
Journal: Cancer Research (2022)

Abstract Mortality from colon and pancreatic cancers arises from cancer metastatic dissemination to the liver. The glycemic load from carbohydrates (carbs) has been specifically linked to the risk of metastatic recurrence of stage 3 colorectal cancer, but the mechanism of how dietary carbs contribute to the formation of liver metastases remains poorly understood. Our analyses now demonstrate that feeding mice a high carb diet (HCD) promotes liver colonization by tumor cells, and supports the survival of these cells, once in the liver. HCD also induces expression of a Type I interferon (IFN) inflammatory gene signatures which may contribute to its ability to promote metastatic seeding of the liver. Notably, this inflammatory phenotype in hepatocytes was completely abolished if animals are fed a diet enriched in fats (75% of calories), indicating a direct link between liver inflammation and consumption of carbohydrates. Specifically, we have discovered that: 1) dietary carbohydrates, but not a high-fat ketogenic diet, activate multiple independent inflammatory cascades in hepatocytes, including Type-I IFN/STAT1, NFkB, and IL6-STAT3 pathways; 2) the inflammatory signaling in hepatocytes is retained in Scid and NSG mice, indicating that it occurs in the absence of adaptive immunity; 3) HCD, but not fasting or ketogenic diet, markedly increases abundance of retained intronic sequences and formation of double-stranded RNA (dsRNAs). We nominate these yet uncharacterized dsRNAs as potential viral mimics which may trigger the Type I IFN signature observed in HCD-fed livers; and (4) a ketogenic diet showed a trend to reduce liver metastatic colonization, but was associated with mild hepatic steatosis. Overall, this study establishes a new paradigm in nutrient sensing by normal hepatocytes and nominates alternative RNA splicing as the potential trigger of inflammatory responses to HCDs via accumulation of dsRNAs. We suggest that a reduction of dietary carbohydrates, by suppressing the diet-induced hepatic inflammation, will improve the survival of cancer patients, and reduce the risk of liver metastases. Citation Format: Aizhan Surumbayeva, Riley Williams, Michael Kotliar, Maryclare Taylor, Débora B. Vendramini Costa, Charline Ogier, Diana Restifo, Kathy Q. Cai, Xueyang He, Paul Boutz, Siddharth Balachandran, Igor Astsaturov. Inflammatory response to dietary carbohydrates contributes to the formation of hepatic metastatic niche [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B019.
Abstract B039: Development of a selective therapeutic intervention for p53 mutant for pancreatic adenocarcinoma
Authors: Mohammed M. Alruwaili, Justin Zonneville, Mohammed A. Alqarni, Priyanka Rajan, Hannah Serio, Robert Straubinger, Christos Fountzilas, Andrei Bakin
Journal: Cancer Research (2022)

Abstract Genetic alterations in the tumor suppressor p53 gene (TP53) are found in over 70% of Pancreatic Adenocarcinoma (PAAD) and contribute to poor prognosis, cancer progression and metastasis. Existing treatment options for p53 mutant (p53mut) cancer are limited and there is an urgent need for better therapeutic interventions that can be greatly beneficial to a large proportion of patients with PAAD. Here we present a novel therapeutic strategy for selective targeting p53mut pancreatic tumors. Genomic data revealed that p53-deficient PAADs express high levels of DNA replication genes as well as genes involved in Base Excision (BER) and Mismatch (MMR) Repair, indicating activation of these mechanisms. Evaluation of BER activity by a novel methodology with a modified deoxyuridine analogue showed a significant dysregulation in BER mediated repair in p53mut cancer cells leading to accumulation of p53mut tumor cells in late S/G2 phase. By exploiting this defect, we found that treatment with a deoxyuridine analogue such as trifluorothymidine (TFT, a component of TAS102) resulted in accumulation of DNA breaks selectively in p53mut cells. A deoxyuridine analogue (TFT) did not block DNA replication but rather activated DNA repair leading to DNA breaks in p53mut cells whereas p53 wild type cells accumulated in G1 with minimal DNA damage. Further, we found that inhibition of poly (ADP) ribose polymerase (PARP) enhanced DNA damage and increased cell death selectively in p53mut tumor cells although PARP inhibitor alone was not effective. In contrast, the TAS102-PARPi did not induce DNA damage in the normal cells such as hTERT-immortalized Human Pancreatic Nestin Expressing cells (HPNE). A new TAS102-PARPi combination regimen demonstrated greater inhibition of tumor growth and improved the survival rates in p53mut PAAD xenograft models including Cell-Derived Xenograft (CDX) and Patient-Derived xenograft (PDX) models, compared to either drug alone without adverse effects in mice. Thus, this preclinical work identified a novel and immediately feasible strategy for p53mut disease that may improve treatment and the quality of life for a significant proportion of patients with PAAD while limiting toxic effects on normal tissues. Citation Format: Mohammed M. Alruwaili, Justin Zonneville, Mohammed A. Alqarni, Priyanka Rajan, Hannah Serio, Robert Straubinger, Christos Fountzilas, Andrei Bakin. Development of a selective therapeutic intervention for p53 mutant for pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B039.
The challenges of doing paediatric research during the first year of the covid-19 pandemic
Authors: Danilo Buonsenso, Damian Roland, Adriana Yock-Corrales, Sebastián González-Dambrauskas, Petter Brodin, Begona Santiago-Garcia, Antoni Soriano-Arandes, Marianne Koenraads, Daniele De Luca, Elizabeth Whittaker
Journal: BMJ (2022)
Abstract B069: Inhibiting pancreatic cancer growth by dual targeting of ERK and PI3K signaling
Authors: Gauthami G. Nair, Katie Reindl, Mohiuddin Quadir
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a dismal 5-year survival rate of only 11%. Due to its late-stage detection and metastasis, surgery is not an option in most cases, and chemotherapy has become the sought-after strategy to combat PDAC. Current treatment strategies involve combining chemotherapeutic agents; however, these drugs show limited response in some patients and frequently result in acquired drug resistance. There is a need for new treatment approaches to more specifically target molecules involved in PDAC growth. The KRAS gene is mutated in almost 95% of the pancreatic cancers resulting in hyperactivated K-ras protein, which activates downstream growth-promoting signaling pathways such as extracellular receptor kinase (ERK) and phosphatidylinositol 3 kinase (PI3K). Thus, we hypothesized that the combination of ERK and PI3K inhibitors would lead to enhanced PDAC growth inhibition compared to either drug alone. To test our hypothesis, we used SCH772984 (an ERK1/2 inhibitor) and pictilisib (a class I PI3K inhibitor) to perform a cell viability assay using human PDAC cell lines, MIA PaCa-2 and PANC-1, for both 2-D cells and 3-D spheroids. Our results indicated that the cancer cells treated with both drugs showed reduced cell proliferation compared to either of the drugs administered individually. Our next steps will involve evaluation of this combination in animal models as well as testing these drugs against clinical PDAC samples. This research may lead to a novel combination of pictilisib and SCH772984 to enhance treatment for PDAC patients. Citation Format: Gauthami G. Nair, Katie Reindl, Mohiuddin Quadir. Inhibiting pancreatic cancer growth by dual targeting of ERK and PI3K signaling [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B069.
Abstract C048: Benzodiazepines modify the pancreatic ductal adenocarcinoma tumor microenvironment
Authors: Abigail C. Cornwell, Abdulrahman A. Alahmari, Arwen A. Tisdale, Kathryn Maraszek, Swati Venkat, Michael E. Feigin
Journal: Cancer Research (2022)

Abstract Benzodiazepines (BZDs) are a class of drugs commonly prescribed to pancreatic ductal adenocarcinoma (PDAC) patients to treat anxiety, anticipatory nausea prior to chemotherapy, and insomnia. We discovered that approximately 1 in 4 pancreatic cancer patients are prescribed BZDs and that significant differences in survival outcomes are associated with the type of BZD prescribed. Lorazepam is associated with poorer recurrence-free survival (HR 3.83 (1.53,9.57)) while alprazolam is associated with improved recurrence-free survival (HR 0.38 (0.16,0.92)). We hypothesize that these differences in survival result from off-target activation of the proton-sensing GPCR, GPR68, by n-unsubstituted BZDs, such as lorazepam. GPR68 is preferentially expressed in PDAC cancer-associated fibroblasts (CAFs). We found that n-unsubstituted BZDs commonly prescribed to PDAC patients potentiate activation of GPR68 in the presence of acidity, subsequently promoting secretion of IL-6 by CAFs in a GPR68-dependent manner. Conversely, we found that n-substituted BZDs, such as alprazolam, decrease IL-6 secretion by CAFs in a GPR68-independent manner. Using a syngeneic KPC transplant model, we found that tumors from mice treated with lorazepam had increased expression of inflammatory signaling pathways and ECM-related genes by RNA sequencing. Histologically, lorazepam-treated tumors had increased levels of collagen, alpha-smooth muscle actin staining, and high levels of ischemic necrosis in the centers of the tumors. Overall, these findings indicate that benzodiazepines can modify the PDAC tumor microenvironment, which may subsequently impact chemotherapeutic efficacy and patient survival. Citation Format: Abigail C. Cornwell, Abdulrahman A. Alahmari, Arwen A. Tisdale, Kathryn Maraszek, Swati Venkat, Michael E. Feigin. Benzodiazepines modify the pancreatic ductal adenocarcinoma tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C048.
Abstract A010: Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC
Authors: Xu Zhou, Roma Kurilov, John P. Neoptolemos, Benedikt Brors, Kai Hu, Teresa Peccerella, Jing-Yu An, Stephanie Roessler, Katrin Pfütze, Angela Schulz, Stephan Wolf, Nicolas Hohmann, Ulrike Heger, Oliver Strobel, Simon T Barry, Christoph Springfeld, Christine Tjaden, Frank Bergmann, Markus Büchler, Thilo Hackert, Franco Fortunato, Peter Bailey
Journal: Cancer Research (2022)

Abstract The impact of neoadjuvant chemotherapy on tumor cells is largely unknown with resistance to therapy remaining a significant challenge. We analyzed 171 chemo-naïve and post-chemotherapy resected patient samples (chemoradiotherapy excluded) using RNAseq and multiplexed immunofluorescence. Neoadjuvant chemotherapy enriched for distinct neoplastic persister phenotypes expressing Classical and Basal-like biomarkers GATA6 and KRT17. The enrichment of GATA6HiClassical-like and KRT17Hi Basal-like cells in post-chemotherapy patient samples was associated with poor survival after mFOLFIRINOX, but not gemcitabine. CYP3A subfamily enzymes (CYP3A4 and CYP3A5) were expressed in GATA6Hi and KRT17Hi persister cells and can degrade mFOLFIRINOX constituent irinotecan. Taken together these data support a model in which pre-existing subpopulations of GATA6Hi (Classical) and/or KRT17Hi (Basal) neoplastic cells emerge after mFOLFIRINOX treatment by expressing CYP3A. The identification of CYP3A-enabled persister cell phenotypes is an important step in the design of effective therapies to overcome drug-tolerance and prevent recurrence after neoadjuvant therapy. Citation Format: Xu Zhou, Roma Kurilov, John P. Neoptolemos, Benedikt Brors, Kai Hu, Teresa Peccerella, Jing-Yu An, Stephanie Roessler, Katrin Pfütze, Angela Schulz, Stephan Wolf, Nicolas Hohmann, Ulrike Heger, Oliver Strobel, Simon T Barry, Christoph Springfeld, Christine Tjaden, Frank Bergmann, Markus Büchler, Thilo Hackert, Franco Fortunato, Peter Bailey. Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A010.
Preclinical evaluation of combination nemtabrutinib and venetoclax in chronic lymphocytic leukemia
Authors: Elizabeth M. Muhowski, Janani Ravikrishnan, Britten Gordon, Lianbo Yu, Shrilekha Misra, Brandi Walker, Sudharshan Eathiraj, Deepa Sampath, Kerry A. Rogers, John C. Byrd, Jennifer A. Woyach
Journal: Journal of Hematology & Oncology (2022)

Abstract Inhibitors of B cell receptor (BCR) signaling such as the Bruton’s tyrosine kinase (BTK) inhibitors are effective therapeutics for chronic lymphocytic leukemia (CLL). The first-in-class covalent BTK inhibitor, ibrutinib, produces durable responses in most CLL patients; however, complete responses are only observed in a minority of patients. B cell lymphoma 2 (BCL2), an anti-apoptotic protein that contributes to CLL cell survival, has also been investigated as a therapeutic target. The BCL2 inhibitor venetoclax is effective in patients with CLL and can produce undetectable minimal residual disease, allowing discontinuation of therapy. In combination, ibrutinib and venetoclax have shown preclinical synergy and clinical efficacy. Nemtabrutinib is a next generation, reversible inhibitor of BTK that potently inhibits BCR signaling in treatment-naïve and ibrutinib-refractory CLL cells ex vivo. The clinical efficacy of combining BTK inhibitors with BCL2 inhibitors motivated us to evaluate the novel combination of nemtabrutinib and venetoclax. In vitro studies show that nemtabrutinib and venetoclax are not antagonistic to each other. In an adoptive transfer CLL mouse model, mice treated with nemtabrutinib and venetoclax had prolonged survival compared to mice treated with ibrutinib and venetoclax. Our preclinical studies further validate the combination of BTK inhibitors with venetoclax and justify further investigation of combining nemtabrutinib with venetoclax in CLL.
Abstract A006: Integrating single cell and spatial transcriptomics define gene signature for pancreatic ductal adenocarcinoma pre-neoplastic lesion
Authors: Ahmed M. Elhossiny, Eileen Carpenter, Padma Kadiyala, Yaqing Zhang, Filip Bednar, Arvind Rao, Timothy Frankel, Marina Pasca Di Magliano
Journal: Cancer Research (2022)

Abstract Pancreatic Cancer Ductal Adenocarcinoma (PDAC) is one of the deadliest cancers with 5-year survival of 11%. Understanding the intratumor heterogeneity is a pivotal piece to unravel the complexity of PDAC. While single cell RNASeq identifies the heterogeneous cell populations within the tumor tissue, spatially characterizing the transcriptomic profile of neoplastic and pre-neoplastic populations within the tissue remains a challenge, as the spatial dimension is usually lost upon tissue dissociation. We identified an approach to integrate spatial transcriptomics data with single cell RNASeq data. To characterize the cell populations within the tissue we performed single cell RNASeq on disease pathology-free pancreas tissue and primary PDAC samples. We profiled the transcriptomic profile of Acinar, Ductal, Acinar-to-Ductal (ADM), and Pancreatic Intraepithelial Neoplasia (PanINs) regions of interest (ROIs) across the tissue using the Nanostring GeoMx platform. Differential gene expression analysis using linear mixed-effect models of the cell-type specific ROIs defined pan-marker gene sets for each cell type, which were mapped to UMAP projections of single cell RNA sequencing data using AUCell scoring. As expected, the acinar pan-markers gene set derived from the spatial transcriptomics mapped to the manually annotated acinar population in the single cell data. On the other hand, Ductal, ADM, and PanIN pan-marker gene sets were mapped to distinct clusters that previously were not well-defined by single cell sequencing. The analysis coupled with orthogonal validation using RNAScope revealed gene signatures uniquely specific to ADM lesions and PanINs, respectively. Interestingly, our list included known markers as well as novel findings, supporting the validity of the findings. Furthermore, RNA velocity analysis using scVelo revealed a trajectory of cell evolution originating from acinar cells passing through the newly-defined ADM population and ending towards the ductal population derived from tumor samples. Overall, this integration approach of spatial and single cell transcriptomics can further define the characteristics that differentiate neoplastic and pre-neoplastic populations, as well as the potential drivers for tumorigenesis that could be therapeutically targeted. Citation Format: Ahmed M. Elhossiny, Eileen Carpenter, Padma Kadiyala, Yaqing Zhang, Filip Bednar, Arvind Rao, Timothy Frankel, Marina Pasca Di Magliano. Integrating single cell and spatial transcriptomics define gene signature for pancreatic ductal adenocarcinoma pre-neoplastic lesion [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A006.
Abstract B080: Disruption of ADAM17-dependent cellular crosstalk inhibits tumor progression of pancreatic ductal adenocarcinoma
Authors: Hui-Ju Wen, Jacee Moore, Erick Davis, Daniel Long, Justin Lee, Brian Devorkin, Howard Crawford
Journal: Cancer Research (2022)

Abstract Activation of cellular signaling pathways by crosstalk between tumor cells and their microenvironment is an essential mechanism supporting pancreatic carcinogenesis. In this study, we aim to disrupt cellular signaling pathways by targeting ADAM17 (a disintegrin and metalloprotease 17). ADAM17 is a membrane bound enzyme which cleaves cell surface proteins. Its function is closely linked with autocrine and paracrine signaling of immunomodulation as well as activation of EGFR, which is a central molecule for pancreatic tumorigenesis. To investigate whether EGFR is activated via a paracrine manner from macrophages, the most abundant immune-related stromal cells in pancreas cancers, we generated a pancreatic tumor mouse model with ADAM17 deletion in myeloid cells by using a dual recombinase strategy. We observed that lack of ADAM17 in the myeloid cells resulted in a delay of acinar cell transformation and an associated decrease in EGFR activation. To further examine the tumor supportive role of ADAM17, systemic inhibition of ADAM17 using anti-ADAM17 antibody, MEDI3622, was tested in orthotopic tumor bearing mice. Systemic blockade of ADAM17 significantly reduced tumor burden and suppressed activation of EGFR and STAT3, which are associated with two pro-tumoral signaling pathways. In addition, we found an elevated level of CCL21 in the MEDI3622-treated tumors resulting in increased tumor infiltration by dendritic cells and cytotoxic T cells as well as low infiltration of G-MDSC (granulocytic myeloid-derived suppressor cells). These results demonstrate a pronounced anti-tumor effect by ADAM17 blockade and indicate ADAM17 as a therapeutic target of pancreatic cancer. Citation Format: Hui-Ju Wen, Jacee Moore, Erick Davis, Daniel Long, Justin Lee, Brian Devorkin, Howard Crawford. Disruption of ADAM17-dependent cellular crosstalk inhibits tumor progression of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B080.
Abstract C082: Signaling pathways inducing tumoricidal phagocytosis in pancreatic cancer
Authors: Li Qiang, Samantha Liu, Gabrielle Ro, Lestat Ali, Patrick Lenehan, Felix Hambizer, Michael Dougan, Stephanie Dougan
Journal: Cancer Research (2022)

Abstract Macrophages can be repolarized to promote tumor destruction, particularly by triggering tumoricidal phagocytosis of cancer cells. Despite the increasing interest in monoclonal antibody therapies targeting tumor antigens to drive cancer cell elimination via phagocidal macrophages, we still face tremendous challenges in developing adequate therapeutics due to lack of knowledge of the signaling pathways that induce phagocidal macrophages. Our previous work showed that cIAP1/2 antagonism and T cell derived cytokines promote anti-tumor immunity by reprogramming tumoricidal macrophages to phagocytose both live and dead tumor cells. Here we performed transcriptional analysis on both macrophages and tumor cells treated with cIAP1/2 antagonism or vehicle and identified candidate positive and negative regulators of phagocytosis. We are demonstrating how these receptors-ligand pairs on macrophages and tumor cells are induced and the mechanisms by which they effect tumor cell destruction. We also performed an in vitro CRISPR screen on tumor cells cocultured with macrophages, treated with cIAP1/2 antagonism or vehicle, recovered the DNA of phagocytosed tumor cells from within macrophages and compared to non-phagocytosed tumor cells to discover mediators of resistance or sensitivity to both baseline phagocytosis (efferocytosis) and cIAP1/2 antagonism induced phagocytosis.Our screen revealed a striking lack of dependence on MHC class I for tumors treated in vivo. Genes involved in phagocytosis resistance instead converged on regulation of the cytoskeleton and the tumor suppressor gene Stk11. This study will provide critical insights on tumoricidal macrophages, uncover the key pathways reprogramming these myeloid cells, and decipher the essential tumor-intrinsic pathways resulting in sensitivity and resistance to anti-tumor phagocytosis. Citation Format: Li Qiang, Samantha Liu, Gabrielle Ro, Lestat Ali, Patrick Lenehan, Felix Hambizer, Michael Dougan, Stephanie Dougan. Signaling pathways inducing tumoricidal phagocytosis in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C082.
Abstract IA011: Precision oncology approaches in pancreatic cancer
Authors: Jen Jen Yeh
Journal: Cancer Research (2022)

Abstract Advances in next generation sequencing and therapies have led to an explosion of possibilities for precision oncology in pancreatic cancer. The talk will focus on current and up and coming precision approaches for patients with pancreatic cancer. Citation Format: Jen Jen Yeh. Precision oncology approaches in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA011.